کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2599547 | 1133216 | 2012 | 9 صفحه PDF | دانلود رایگان |
CYP1A1 and CYP1A2 are involved in both detoxification and metabolic activation of xenobiotics. Human CYP1A1 (hCYP1A1) and hCYP1A2 exist in a head-to-head orientation in chromosome 15 with the overlapping 5′-flanking region. We have recently reported that nuclear receptor constitutive androstane receptor (CAR), in addition to aryl hydrocarbon receptor, bidirectionally transactivates these genes through common motifs. In this study, we have investigated a role of liver X receptor α (LXRα), another liver-enriched nuclear receptor, in the expression hCYP1A1 and hCYP1A2. In reporter assays with dual-reporter constructs containing their promoter region between two different reporter genes, LXRα simultaneously transactivated hCYP1A1 and hCYP1A2 through two regions, independent of aryl hydrocarbon receptor. In electrophoretic mobility shift assays, LXRα/retinoid X receptor α heterodimer bound to two ER8-type motifs found at around −520 and −460 of hCYP1A1. The former corresponds to the CAR-binding motif previously identified. Reporter assays using mutated constructs confirmed the critical roles of these motifs in the LXRα-mediated simultaneous transcription of hCYP1A1 and hCYP1A2. hCYP1A1 and hCYP1A2 mRNA levels were increased in human hepatoma HuH-7 cells and human primary hepatocytes, respectively, after treatment with the LXRα ligand GW3965. Our results suggest that LXRα transactivates the expression of hCYP1A1 and hCYP1A2 through common two cis-elements.
► LXRα activation induced transactivation of both hCYP1A1 and hCYP1A2 simultaneously.
► LXRα-mediated transactivation of hCYP1A1 and hCYP1A2 is through two regions.
► LXRα/RXRα heterodimer binds to two ER8 motifs in the proximal promoter of hCYP1A1.
► LXRα synergistically transactivated hCYP1A1 and hCYP1A2 with AhR but not CAR.
► LXRα ligand increased hCYP1A1 and hCYP1A2 mRNA levels in a cell-specific manner.
Journal: Toxicology Letters - Volume 215, Issue 1, 23 November 2012, Pages 16–24